Stereoselective synthesis of 1,2-aminoalcohols by [2,3]-wittig rearrangements

Article abstract of DOI:10.1021/ol0711725

[2,3]-Wittig rearrangements of (E)-3-aza-allylic alcohol derivatives can provide access to functionalized 1,2-aminoalcohols with high syn or anti diastereoselectivity depending on the anionic stabilizing group (amide or alkyne). American Chemical Society.

Full text of DOI:10.1021/ol0711725

ORGANIC
LETTERS
2007
Vol. 9, No. 17
3245-3248
Stereoselective Synthesis of
1,2-Aminoalcohols by [2,3]-Wittig
Rearrangements
Marion Barbazanges, Christophe Meyer,* and Janine Cossy
Laboratoire de Chimie Organique, ESPCI, CNRS, 10 rue Vauquelin
75231 Paris Cedex 05, France
christophe.meyer@espci.fr
Received May 18, 2007
ABSTRACT
[2,3]-Wittig rearrangements of (E)-3-aza-allylic alcohol derivatives can provide access to functionalized 1,2-aminoalcohols with high syn or anti
diastereoselectivity depending on the anionic stabilizing group (amide or alkyne).
1,2-Aminoalcohols are encountered in a large number of
natural products and/or biologically active compounds.1
Moreover, optically enriched 1,2-aminoalcohols are often
used as building blocks for the preparation of chiral catalysts
used in a variety of enantioselective processes.2 Numerous
strategies have been developed to synthesize 1,2-aminoal-
cohols. Among the different possible routes, those that
involve formation of the σ bond between the two hetero-
substituted carbons, with control of their configuration,
essentially rely on the addition of R-amino or R-alkoxy
carbon nucleophiles to carbonyl compounds or imines.3,4
Alternatively, reductive coupling reactions between CdN and
CdO bonds can also be carried out.5 The preparation of
R-alkoxy-â-aminoesters has also been described from
R-alkoxy-γ,δ-unsaturated esters that can be obtained by a
[3,3]-glycolate Claisen rearrangement. In this latter approach,
oxidative cleavage of the double bond to the corresponding
acid and subsequent Schmidt reaction were used to introduce
the amino substituent.6 However, to our knowledge, there
are no examples of direct formation of the σ bond between
the two heterosubstituted carbons in 1,2-aminoalcohols that
relies on sigmatropic rearrangements. Herein, we report our
results on the [2,3]-Wittig rearrangement of derivatives of
(3) For selected references, see: (a) Ramasastry, S. S. V.; Zhang, H.;
Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2007, 129, 288-289. (b)
Trost, B. M.; Jaratjaroonphong, J.; Reutrakul, V. J. Am. Chem. Soc. 2006,
128, 2778-2779. (c) Carswell, E. L.; Snapper, M. L.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2006, 45, 7230-7233. (d) Enders, D.; Grondal, C.;
Vrettou, M.; Raabe, G. Angew. Chem., Int. Ed. 2005, 44, 4079-4083. (e)
Matsunaga, S.; Yoshida, T.; Morimoto, H.; Kumagai, N.; Shibasaki, M. J.
Am. Chem. Soc. 2004, 126, 8777-8785. (f) List, B.; Pojarliev, P.; Biller,
W. T.; Martin, H. J. J. Am. Chem. Soc. 2002, 124, 827-833.
(4) (a) Lombardo, M.; Mosconi, E.; Pasi, F.; Petrini, M.; Trombini, C.
J. Org. Chem. 2007, 72, 1834-1837. (b) Keinicke, L.; Fristrup, P.; Norrby,
P.-O.; Madsen, R. J. Am. Chem. Soc. 2005, 127, 15756-15761. (c) Reetz,
M. T. Chem. ReV. 1999, 99, 1121-1162. (d) Bloch, R. Chem. ReV. 1998,
98, 1407-1438 and references cited in these articles.
(1) (a) Lee, H.-S.; Kang, S. H. Synlett 2004, 1673-1685. (b) Bergmeier,
S. C. Tetrahedron 2000, 56, 2561-2576. (c) Ager, D. J.; Prakash, I.; Schaad,
D. R. Chem. ReV. 1996, 96, 835-875. (d) Cardillo, G.; Tomasini, C. Chem.
Soc. ReV. 1996, 117-128. (e) Cole, D. C. Tetrahedron 1994, 50, 9517-
9582.
(2) (a) Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; ComprehensiVe
Asymmetric Catalysis, 1st ed.; Springer: Berlin, 1999. (b) Fache, F.; Schulz,
E.; Tommasino, M. L.; Lemaire, M. Chem. ReV. 2000, 100, 2159-2232.
(5) Zhong, Y.-W.; Dong, Y.-Z.; Fang, K.; Izumi, K.; Xu, M.-H.; Lin,
G.-Q. J. Am. Chem. Soc. 2005, 127, 11956-11957 and references cited
therein.
(6) Jung, D. Y.; Kang, S.; Chang, S.; Kim, Y. H. Synlett 2006, 86-90.
10.1021/ol0711725 CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/27/2007

acyclic 3-aza-substituted allylic alcohols as a diastereose-
lective route to 1,2-aminoalcohols.
Table 1. Synthesis of 3-aza-Allylic Alcohols of Type C
With the goal of synthesizing R-hydroxy-â-amino-γ,δ-
unsaturated carbonyl derivatives of type A, in which the
double bond and the carbonyl group could undergo several
transformations and hence give access to a variety of
functionalized 1,2-aminoalcohols, it was envisaged to carry
out the [2,3]-Wittig rearrangement of enamine derivatives
of type B.7 The latter compounds would be synthesized from
the 3-aza-allylic alcohols of type C. Although there has been
one previous report dealing with [2,3]-Wittig rearrangements
of substrates bearing an enol ether moiety,8 related reactions
have apparently not been studied with enamine derivatives.
As compounds of type B contain an enamine moiety and a
potential allylic alkoxy leaving group, the nitrogen atom was
substituted by an electron-withdrawing tosyl substituent (R′
) Ts) to obtain stable enamide derivatives (Scheme 1).
1
R
(E)/(Z)a
2
yield (%)b
3
yield (%)
1a Bn
92:8
2a
2b
2c
2d
2e
2f
91
69
82
84
90
55
3a
3b
3c
3d
3e
3f
95
99
94
99
93
84
1b CH2CH(OMe)2
1c (CH2)2CHdCH2
1d CH2CHdCH2
1e PMB
87:13
82:18
88:12
90:10
70:30
1f PMP
a
1
b
Determined by H NMR and/or GC-MS. Isolated yield of the (E)
isomer.
ynamide 5 afforded the propargylic alcohol 6 which could
be stereoselectively reduced (Red-Al, THF, rt) to the
corresponding (E)-allylic alcohol 3a (68%, two steps from
5) (Scheme 2).
Scheme 1. Synthesis of R-Hydroxy-â-aminocarbonyl
Compounds by [2,3]-Wittig Rearrangement
Scheme 2. Stereoselective Synthesis of 3-aza-Allylic Alcohols
A straightforward route toward allylic alcohols of type C
starts with the conjugate addition of sulfonamides 1a-f to
methyl propiolate in the presence of N-methylmorpholine
(NMM) (MeCN, 0 °C).9 The corresponding â-aminoacrylates
were obtained as a mixture of geometric isomers with
acceptable stereoselectivity in most cases [(E)/(Z) g 80:20]
except when R is a p-anisyl group [(E)/(Z) ) 70:30].
After separation by flash chromatography, the major
(E)-â-aminoacrylates 2a-f were isolated in good yields
(55-91%) and were reduced (DIBAL-H, CH2Cl2, -78 °C)
to the corresponding (E)-allylic alcohols 3a-f (84-99%)
without alteration of the stereoisomeric purity (Table 1).
Though this access to 3-aza-allylic alcohols of type C was
convenient, a stereoselective route to both geometric isomers
of the latter compounds has also been secured. The copper-
catalyzed coupling between sulfonamide 1a and bromoalkyne
4 [CuSO4‚5H2O, 1,10-phenanthroline, K3PO4, toluene, 60 °C]
afforded the disubstituted ynamide 5 (99%).10 The latter
was reduced to the (Z)-allylic alcohol 7 by conversion to an
(η2-alkyne)Ti(II) complex followed by hydrolysis11 and sub-
sequent deprotection with TBAF (59%, two steps from 5).
On the other hand, deprotection of the hydroxyl group in
The 3-aza-substituted allylic alcohols had to then be
converted to allylic ethers of type B, required as substrates
for the [2,3]-Wittig rearrangement, and derivatives bearing
a carbonyl amide group were first considered.12 Thus,
alcohols 3a-f were alkylated with N-(bromoacetyl)pyrroli-
dine 8 under phase-transfer catalysis (35% aq NaOH/toluene,
cat. n-Bu4NHSO4) to provide amides 9a-f in good yields
(85-99%) (Table 2).
Metalation of amides 9a-f was achieved by treatement
with LiHMDS (1.5-2 equiv, THF, -40 °C to 0 °C; method
A), and subsequent [2,3]-Wittig rearrangement took place
to afford mixtures of the corresponding diastereomeric syn-
and anti-R-hydroxy-â-amino amides 10a-f and 11a-f,
respectively, with low to good diastereoselectivities (syn/
anti ) 2:1 to 10:1).13 To improve these results, the effect of
additives was investigated. Addition of the polar cosolvent
(7) (a) Frauenrath, H. In Houben-Weyl (Methods of Organic Chemistry),
StereoselectiVe Synthesis; Helmchen, G.; Hoffmann, R. W., Mulzer, J.,
Schaumann, E., Thieme Verlag: Stuttgart, 1995; Vol. E21d, pp 3301-
3756. (b) Nakai, T.; Mikami, K. Chem. ReV. 1986, 86, 885-902. (c)
Marshall, J. A. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: London, 1991; Vol. 3, pp 975-908.
(8) Nakai; E.; Nakai, T. Tetrahedron Lett. 1988, 29, 5409-5412.
(9) Lee, E.; Kang, T. S.; Joo, B. J.; Tae, J. S.; Li, K. S.; Chung, C. K.
Tetrahedron Lett. 1995, 36, 417-420.
(10) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E.
L. Org. Lett. 2004, 6, 1151-1154.
(11) (a) Tanaka, R.; Hirano, S.; Urabe, H.; Sato, F. Org. Lett. 2003, 5,
67-70. (b) (η2-ynamide)Ti(II) complexes also react with aldehydes to afford
3-aza-allylic alcohols having a trisubstituted double bond: Hirano, S.;
Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6, 727-729.
(12) Mikami, K.; Takahashi, O.; Kasuga, T.; Nakai, T. Chem. Lett. 1985,
1729-1732.
3246
Org. Lett., Vol. 9, No. 17, 2007

To prepare propargylic ethers from the alcohols 3a-e, a
two-step procedure involving alkylation with propargyl
bromide under phase-transfer catalysis followed by silylation
of the terminal alkyne moiety (n-BuLi, THF, -78 °C) was
initially used (method C, Table 4). Under these conditions,
alcohols 3a and 3b were efficiently converted to ethers 12a
(67%) and 12b (91%), respectively, but 12c was obtained
in low yield (31%) from 3c.15 A one-step propargylation
protocol of alcohols 3c-e (method D, Table 4) was therefore
developed under phase transfer conditions with the propar-
gylic bromide 13, bearing a TIPS group, and the propargylic
ethers 14c-e were thus obtained in high yields (86-91%)
(Table 4).
Table 2. Synthesis of Amides 9
3
R
9
yield (%)
3a
3b
3c
3d
3e
3f
Bn
9a
9b
9c
9d
9e
9f
96
97
99
85
86
97
CH2CH(OMe)2
(CH2)2CHdCH2
CH2CHdCH2
PMB
PMP
Table 4. Synthesis of the Propargylic Ethers 12 and 14
HMPA (4 equiv) enabled us to achieve the deprotonation
of amides 9a-f at a lower temperature (LiHMDS, THF,
-78 °C; method B), and under these conditions, subsequent
[2,3]-Wittig rearrangements occurred with a dramatic im-
provement of the diastereoselectivity (syn/anti ) 9:1 to >24:
1) (Table 3).
3
R
method
R′
12/14
yield (%)
3a
3b
3c
Bn
C
C
C
D
D
D
TMS
TMS
TMS
TIPS
TIPS
TIPS
12a
12b
12c
14c
14d
14e
67
84
31
86
89
91
Table 3. [2,3]-Wittig Rearrangements of Amides 9
CH2CH(OMe)2
(CH2)2CHdCH2
3d
3e
CH2CHdCH2
PMB
Despite the presence of other potential acidic hydrogens
in substrates 12a-c and 14c-e, metalation at the propargylic
position was successfully achieved by treatment with LDA
(THF, -78 °C), and subsequent [2,3]-Wittig rearrangements
proceeded cleanly to afford the corresponding 1,2-aminoal-
cohols 15a-c and 16c-e in good yields (74-93%) and
with high 1,2-anti diastereoselectivity (anti/syn ) 11:1 to
>24:1). It is interesting that the propargylic ethers 14c-e
substituted by a TIPS group are not only easier to synthesize
but also also underwent [2,3]-Wittig rearrangements with
higher diastereoselectivities (dr > 24:1) (Table 5).16
Additionally, it is also noteworthy that the rearrangement
of propargylic ethers derived from (E)-3-aza-allylic alcohols
can also provide access to anti-R-hydroxy-â-amino methyl
ketones of type A (R′′ ) Me). Indeed, the triple bond in
compound 15a can undergo hydration (cat. HgSO4, cat.
H2SO4, THF/H2O, rt) to afford ketone 17 (86%) without
epimerization (Scheme 3).
method A
method B
syn/anti
(10/11)
yield
(%)
syn/anti
(10/11)
yield
(%)
R
9a
9b
9c
9d
9e
9f
Bn
7:1
3:1
6:1
10:1
6:1
2:1
73
61
60
58
66
55
>24:1
19:1
>24:1
>24:1
>24:1
9:1
77
64
71
75
49
52
CH2CH(OMe)2
(CH2)2CHdCH2
CH2CHdCH2
PMB
PMP
Attempts to achieve the rearrangements of amides of type
B synthesized from 3-aza-allylic alcohols of (Z) configura-
tion, which may have potentially reverted the diastereose-
lectivity in favor of the anti-R-hydroxy-â-amino amides 11,
have not yet been successful.14 Thus, with the aim of getting
access to 1,2-anti-aminoalcohols by [2,3]-Wittig rearrange-
ments of derivatives of (E)-3-aza-allylic alcohols, the
remaining option was to replace the π-acceptor amide group
by a stabilizing π-donor alkynyl substituent.
The stereochemical outcome observed in the [2,3]-rear-
rangement of the amides and the propargylic ethers derived
from 3-aza-allylic alcohols is in perfect agreement with the
(13) The relative configurations of 10a, 11a, and 10f were unambiguously
ascertained by chemical correlations; see Supporting Information. The
relative configuration of the other compounds 10b-e was assigned by
analogy.
(14) The [2,3]-Wittig rearrangement of the pyrrolidine amide derived
from the (Z)-allylic alcohol 7 failed and resulted in extensive decomposition.
Enolization of this substrate appears to be considerably more difficult to
achieve, probably for steric reasons.
(15) For this substrate, metalation of the aromatic group also took place
as a side reaction during the second stage of method C.
(16) The relative configuration of 15a was unambiguously ascertained
by a chemical correlation, and those of 15b,c were assumed to be similar.
Desilylation of 15c and 16c (TBAF, THF) led to the same 1,2-aminoalcohol
indicating that the nature of the silicon substituent on the alkyne does not
affect the stereochemical outcome; see Supporting Information.
Org. Lett., Vol. 9, No. 17, 2007
3247

Scheme 4. [2,3]-Wittig Rearrangements of the Derivatives of
3-aza-Allylic Alcohols of Type C
Table 5. [2,3]-Wittig Rearrangements of Propargylic Ethers
12/14
R
R′
15/16 anti/syn yield (%)
12a
12b
12c
14c
14d
14e
Bn
CH2CH(OMe)2
(CH2)2CHdCH2 TMS
(CH2)2CHdCH2 TIPS
CH2CHdCH2
PMB
TMS
TMS
15a
15b
15c
16c
16d
16e
13:1
23:1
11:1
>24:1
>24:1
>24:1
89
81
74
76
79
93
TIPS
TIPS
transition state model used to rationalize the diastereoselec-
tivities of the rearrangement of nonheterosubstituted alcohol
derivatives. In this five-membered ring transition state model
We have reported the first examples of [2,3]-Wittig
rearrangements of acyclic 3-aza-substituted allylic alcohol
derivatives that proceed with synthetically useful levels of
1,2-diastereoselectivity. Further work is currently underway
to explore the scope of such [2,3]-Wittig rearrangements and
in particular to control the absolute configuration of the
newly formed heterosubstituted stereocenters by the use of
a chirality transfer from secondary 3-aza-allylic alcohols.
Scheme 3. Hydration of Alkyne 15a
Acknowledgment. Financial support from Glaxo-Smith-
Kline and the CNRS (BDI grant to M.B.) is gratefully
acknowledged.
of envelope conformation, the π-donating stabilizing alkynyl
group (of small steric demand) tends to occupy an exo
orientation, whereas an endo orientation is favored for the
π-acceptor amide moiety due to secondary orbital or
electrostatic interactions with the negatively charged olefinic
moiety (Scheme 4).17
Supporting Information Available: Experimental pro-
cedures, analytical data for all new compounds, evidence
1
for stereochemical assignments, and copies of the H and
13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(17) (a) Wu, Y.-D.; Houk, K. N.; Marshall, J. A. J. Org. Chem. 1990,
55, 1421-1423. (b) Mikami, K.; Uchida, T.; Hirano, T.; Wu, Y.-D.; Houk,
K. N. Tetrahedron 1994, 50, 5917-5926.
OL0711725
3248
Org. Lett., Vol. 9, No. 17, 2007